Zika virus (ZIKV) emerged in the Americas in 2015 and has since been recognized to cause neurodevelopmental defects including vision and hearing loss, seizures, microcephaly, and fetal demise (congenital Zika syndrome). ZIKV is now endemic throughout Latin America and the Caribbean, where the related flavivirus dengue virus (DENV), is highly prevalent, transmitted by the same mosquito vector. DENV and ZIKV share significant antigenic cross-reactivity but these cross-reactive antibodies are not cross-neutralizing, creating the potential for DENV antibodies to impact ZIKV transmission and disease. ZIKV also can be transmitted through sexual contact and either transmission route may result in congenital disease. Neutralizing IgG antibodies are important for protection from mosquito-borne transmission and in preliminary studies, humoral immunity appears to be the most important adaptive immune component in restricting vaginal ZIKV infection. IgG-coated viral particles can be trapped in vaginal mucus by IgG-mucin interactions, allowing non-neutralizing IgG to contribute to protection against sexually transmission.
In Aim 1 I will test my hypothesis that both neutralizing and non-neutralizing IgG contribute to protection from ZIKV intravaginal infection. I will image IgG-bound ZIKV in vaginal mucus, study ZIKV binding epitopes of IgG in human genital secretions, and determine if both neutralizing and non-neutralizing monoclonal IgG can protect against ZIKV intravaginal inoculation in a mouse model. IgG is actively transported across the placenta via the neonatal Fc receptor (FcRn), expressed in syncytiotrophoblasts. FcRn binds to IgG at a slightly acidic pH and redirects endosomal IgG away from lysosomal degradation. This mechanism contributes to transplacental transmission of human cytomegalovirus (HCMV). ZIKV cell entry is pH sensitive, so transcytosis by this mechanism requires IgG-bound ZIKV to remain infectious during endosomal acidification long enough to be rescued by FcRn.
In Aim 2 I will test my hypothesis that in DENV immune women, ZIKV bound to cross-reactive but non-neutralizing antibodies can ?hitchhike? across the placenta via FcRn mediated transcytosis. I will use a Transwell culture model to study FcRn- dependent transcytosis, and fusion assays and microscopy to determine pH of fusion for ZIKV.
I aim to characterize the role of DENV antibodies in vector-independent transmission of ZIKV, a paradigm change for flavivirus serology, a project within the goals of the NIAID. Enclosed is also a training plan for myself to obtain an MD/PhD, with research support through Dr. Helen Lazear and Dr. Aravinda de Silva, who together have extensive experience studying flavivirus immunity. During graduate school, I will be seeing patients with Dr. Sylvia Becker-Dreps at a rural clinic in North Carolina, a large proportion of which only speak Spanish. Additionally, I will be traveling to Peru under Dr. Natalie Bowman to collect samples for this proposal. This proposal will train me for a career in global infectious disease research as a physician scientist.
Zika virus (ZIKV) transmitted either sexually or transplacentally in the context of pregnancy might result in congenital defects. Antibodies generated after dengue virus infection cross-react with ZIKV but do not protect against mosquito-dependent transmission. The experiments in this proposal will address whether prior DENV infection can impact vector-independent ZIKV transmission, which could lead to the development of DENV vaccines that account for both risk and protection against ZIKV in DENV-endemic areas.
